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1From the Laboratory of Molecular and Developmental Biology and the 2Section of Molecular Structure and Function, National Eye Institute, National Institutes of Health, Bethesda, Maryland; and 3Molecular Endocrinology and Oncology, Laval University Medical Research Center, Quebec City, Quebec, Canada.
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METHODS. RNA was extracted from dissected human TM and used to construct unamplified, un-normalized cDNA libraries in the pSPORT1 vector. More than 4000 clones were sequenced from the 5' end. Clones were clustered and identified using GRIST software. In addition, the expression patterns of genes encoding olfactomedin-domain proteins were analyzed by RT-PCR.
RESULTS. After non-mRNA contaminants were removed, 3459 independent TM-expressed clones were obtained. These were grouped in 1888 clusters, potentially representing individual expressed genes. Transcripts for the myocilin gene, a locus for inherited glaucoma, formed the third most abundant cluster in the TM collection, and several other genes implicated in glaucoma (PITX2, CYP1B1, and optineurin) were also represented. One abundant TM transcript was from the gene for the angiopoietin-like factor CTD6, which is located at on the long arm of chromosome 1, area 36.2-36.1 in the region of the glaucoma locus GLC3B, whereas other transcripts were from genes close to known glaucoma loci. The TM collection contains cDNAs for genes that are preferentially expressed in the lymphatic endothelium (matrix Gla protein, apolipoprotein D precursor, and selenoprotein P precursor). In addition to EST profiling, RT- PCR was used to detect transcripts of the olfactomedin-domain proteins latrotoxin receptor Lec3 and optimedin in the TM.
CONCLUSIONS. The TM libraries are a good source of molecular markers for TM and candidate genes for glaucoma. The abundance of myocilin cDNAs corresponds to the critical role of this gene in glaucoma and contrasts with libraries derived from cultured tissue. The expression profile raises the possibility that cells of the TM and Schlemm’s canal may be more similar to lymphatic, rather than blood vascular endothelium.
The aqueous humor outflow system is located at the junction of the cornea and iris and consists of the trabecular meshwork (TM) and Schlemm’s canal (SC), leading to the episcleral venous system. The TM and SC are complex structures composed of morphologically and functionally distinct cell types. In particular, the corneoscleral part of the TM consists of beams of connective tissues covered on both surfaces by endothelial-like cells.1 The juxtacanalicular meshwork, which is located just below the SC, is a nontrabecular connective tissue containing three to five layers of star-shaped cells. Together with the inner wall of Schlemm’s canal, this meshwork is thought to compose the region of main resistance to aqueous outflow.2 3 This complexity is reflected in the differing embryonic origins of TM and SC cell types. Cells of the corneoscleral TM are derived from the neural crest, whereas cells of the juxtacanalicular meshwork may be derived from the perivascular cells of Rouget.4 It is thought that the endothelial cells of the SC have a vascular origin.5 6 7
Mutation or altered expression of genes expressed in the TM could interfere with normal function of the tissue, thereby leading to glaucoma. Indeed, three genes associated with different forms of open-angle glaucoma, CYP1B1, myocilin (MYOC), and optineurin, are all expressed in human TM.8 9 10 11 12 13 However, although expression of MYOC is higher in human TM and sclera than in other tissues,9 none of these genes is tissue specific.
A catalog of the transcriptional repertoire of the TM would be of great value to increase our understanding of the function of the tissue and to help in the selection of candidate genes for inherited glaucoma. One powerful technique for investigating the expression profile of tissues or cell types is expressed sequence tag (EST) analysis.14 15 The NEIBank project of the National Eye Institute has been undertaken to produce a molecular encyclopedia of the eye. As part of this effort, EST analyses of several human eye tissues have already been performed.16 17 18 19 20 21 Until now, there has been little information available on the gene expression profile of native human TM. Gonzalez et al.22 have described 833 clones from a PCR-amplified cDNA library constructed from the TM of perfused human eye. Among the first 20 most highly expressed genes, they noted genes encoding glycolytic enzymes (glyceraldehyde-3-phosphate-dehydrogenase [GAPDH], lactate dehydrogenase A [LDHA], and triosephosphate isomerase [TPI]), matrix GLA, chitinase 3-like 1, apolipoprotein D, small inducible cytokine (SCYA20), regulator of G-protein signal, stromelysin 1, and two uncharacterized genes KIAA0258 and DKFZp586O0118. This analysis surprisingly identified no clones for MYOC or for some other glaucoma-related genes, which suggests that culturing of tissue and amplification of mRNA may have produced a profile that does not closely match that of the native TM.
Herein, we present characterization of 3429 cDNA clones from unamplified cDNA libraries derived from freshly isolated human TM. Several genes implicated in glaucoma, including MYOC, optineurin, PITX2, and CYP1B1, are present in this library. The collection also contains cDNA for several potential candidate genes located close to known glaucoma loci in the human genome.
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Materials and Methods |
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The removal of TM tissues from the anterior angle is a delicate procedure. Rigorous measures were thus followed to minimize contamination of the dissected TM by surrounding tissues. In particular, eyes were not included in our study when there were difficulties in dissecting the TM from Schlemm’s canal, iris, or cornea. Even though such procedures were used, a very small amount of cDNA clones derived from nearby cells may be present in our TM library.
The tissues were mixed in denaturing buffer (4 M guanidinium thiocyanate, 25 mM sodium citrate [pH 7] and 0.5% N-lauroylsarcosine) before phenol-chloroform extraction. The RNA was then precipitated using isopropanol, washed in 70% diethyl pyrocarbonate (DEPC)-treated ethanol, and resuspended in DEPC-treated water. RNA from each dissected tissue was analyzed separately by agarose gel electrophoresis to judge quality. Samples of good quality were combined, and 40 µg of total RNA was used for cDNA synthesis. Poly(A)+ RNA was prepared using an oligo(dT) cellulose affinity column.
cDNA Library Construction
The cDNA, directionally cloned in the pSPORT1 vector (Life Technologies, Rockville, MD), was constructed at Bioserve Biotechnology (Laurel, MD). General details of library construction for NEIBank cDNA libraries are described elsewhere.18 19 20 21 In this case, as an additional measure to remove small contaminant fragments, the cDNA was run over a resin column (Sephacryl S-500 HR; Gibco BRL, Grand Island, NY) designed to fractionate cDNA more than 500 bp. The columns were run in TEN buffer, containing 10 mM Tris-HCl (pH 7.5), 0.1 mM EDTA, and 25 mM NaCl. Sublibraries (designated ho, hp, and hq) were made from the first three 35-µL fractions, containing cDNA.
cDNA Sequencing and Bioinformatics
Methods for sequencing and bioinformatics analysis are described in detail elsewhere.19 21 23 24 Briefly, randomly picked clones were sequenced at the NIH Intramural Sequencing Center (NISC). Clones were sequenced from the 5' end. A specially developed software tool, GRIST (Grouping and Identification of Sequence Tags) was used to analyze the data and assemble the results in Web page format.25 Clusters of sequences were also examined (SeqMan II; DNAstar, Madison, WI) to determine alternative transcripts. Sequences were searched through genome resources at the National Institutes of Health (http://www.ncbi.nlm.nih.gov/) and the University of California at Santa Cruz (http://genome.ucsc.edu/; Human Genome Browser provided in the public domain by UCSC Genome Bioinformatics).
PCR Methods
Total RNA (1 µg) was used for cDNA synthesis with commercial reverse transcriptase (SuperScript; Gibco BRL) and oligo(dT)-primer. The amount of synthesized cDNA was evaluated by PCR using primers specific for cyclophilin (5'-TCCTGCTTTCACAGAATTATTCC-3' and 5'-ATTCGAGTTGTCCACAGTCAGC-3'). PCR reactions were performed in a thermal cycler (PTC-200; MJ Research, Watertown, MA) with Taq polymerase (AmpliTaq; Applied Biosystems, Foster City, CA). Each PCR reaction was repeated at least twice. The thermal cycling parameters were as follows: 1 minute 30 seconds at 94° followed by 30 cycles of 25 seconds at 94°, 1 minute 30 seconds at 58°, and 1 minute at 72° and a final incubation for 5 minutes at 72°. PCR reaction products were analyzed by agarose gel-electrophoresis. After adjustment of cDNA concentration, relative abundance of mRNAs was estimated for myocilin (primers 5'-CTTATGACACAGGCACAGGTAT-3' and 5'-GTGACCATGTTCATCCTTCTGG-3'), optimedin (5'-AGGCCTATCATGTCCTTGTCAT-3' and 5'-CAGCACCGCATCAGAGAATTG-3'), olfactomedin-1 (5'-CCATTGCAGTGCCGTTTCTTG-3' and 5'-ACTACGGCATTGCATTTACAACAA-3'), latrotoxin receptor Lec3 (5'-CCTCACTATATATCTTTATGCAGT-3' and 5'-GACCTTCCAATGCTTACGAGG-3'), and olfactomedin-2 (5'-CCCTGTTTCACGTCATCAGCA-3' and 5'-AACTGGAGAACCAGAGCCATAA-3').
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Gene Expression Profile of Human TM and Glaucoma Candidate Genes
Many of the most abundant cDNAs in the TM collection such as, vimentin, elongation factor 1
, translationally controlled tumor protein, and various ribosomal proteins, are also abundant in other cDNA libraries (Table 1) . However among the most abundant TM cDNAs, there are also clones for two genes associated with glaucoma. MYOC is represented by 28 clones, corresponding to approximately 1% of the total sequenced. Until now, MYOC has been found at high abundance only in a subtracted human ciliary body cDNA library,26 which suggests a significant tissue preference for this gene in TM.27 Another gene, PITX2, which is the locus of Rieger syndrome, including malformation of the anterior chamber of the eye and glaucoma,28 was also highly expressed in the human TM, being represented by six clones (Table 1) . Among other abundant clones, those for the extracellular matrix Gla protein are also present at a frequency of approximately 1%. Transcripts for the same gene were highly abundant in cDNA libraries obtained from perfused human eye TM and from human corneal endothelial cells.16 22
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Glaucoma Genes
At least eight loci have been implicated in different forms of glaucoma, and so far three genes have been identified.40 All three of these genes, MYOC, CYP1B1, and OPTN, are represented in the TM collection (Table 4) . Other genes contribute to glaucoma as part of wider syndromes. As mentioned earlier, PITX2, the locus of Rieger syndrome is also represented by six cDNAs. Similarly, mutations in the wolframin gene encoding a transmembrane protein may lead to Wolfram syndrome, which in some cases is associated with juvenile glaucoma,41 and a single cDNA for wolframin is in the TM collection.
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Expression of Genes Encoding the Olfactomedin Domain in the Eye Tissues
To validate the high levels of expression of MYOC in TM implied by the abundance of the cDNA, RT-PCR was used. We have demonstrated that myocilin may interact with another olfactomedin-containing protein, optimedin, through the olfactomedin domain.35 In the collection of cDNAs sequenced for this study, no clones for other known olfactomedin domain-encoding genes were present, and RT-PCR was therefore also used to examine the expression pattern of some olfactomedin-encoding genes in several eye tissues and brain (Fig. 1) .
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Several cDNA libraries from different eye tissues having different embryonic origin and function have recently been characterized.16 18 19 20 21 44 Some of these might be expected to share some similarities with the TM. For example, the filtering cells of the TM share a neural crest origin with corneal endothelial cells. However, although cDNAs corresponding to ribosomal proteins involved in protein synthesis are abundant in both human corneal endothelial cells16 and TM, the complement of other abundant clones is quite different in the two tissues. Prostaglandin D2 synthase is the most prevalent transcript in the corneal cDNA library, and only cDNAs for matrix Gla protein and translationally controlled tumor protein were present in the list of the abundant clones in both libraries.16 It is noteworthy that mRNA sequences for another extracellular matrix protein, decorin, were abundant in the human TM library and human Fuchs’ corneal endothelial SAGE library (see UniGene Cluster Hs. 76152; http://www.ncbi.nlm.nih.gov/UniGene; provided in the public domain byNCBI). The iris is another specialized tissue of the anterior segment of the eye in proximity to the TM. The iris contains several different cell types, plays a critical role in eye development and function, and may also be involved in several eye disorders including glaucoma.46 Although there is overlap in the expression of many genes between the TM and the iris, the lists of the most abundant transcripts in the two tissues are different (see Table 1 in this article and Table 1 in Ref. 19 ). Differences in the most abundant transcripts between the iris, cornea, and TM serve as another indication that the TM samples used for cDNA library construction were not significantly contaminated by the surrounding tissues.
MYOC clones were identified in human iris and also in RPE/choroid cDNA libraries but not in the retina or lens cDNA libraries. This agrees with the results of RT-PCR described herein, in which MYOC was amplified from iris and RPE/choroid, but not from retina or lens (Fig. 1) . The high abundance of MYOC transcripts in TM compared with other tissues in the eye and elsewhere correlates with the observation that glaucoma-causing mutations in this gene do not lead to disease elsewhere in the body. Myocilin contains an olfactomedin domain, through which it can interact with other olfactomedin domain proteins. The present collection of TM cDNAs does not contain any clones for any other identified proteins of this family. However, we checked for the expression of some other olfactomedin domain genes by RT-PCR. In the human eye, expression of MYOC corresponds most closely with that of the latrotoxin receptor, Lec3.42 It is interesting that cDNAs for both myocilin and another member of the latrotoxin receptor family, lectomedin, have been detected in the human fetal cochlea (http://neibank.nei.nih.gov/). We are now testing possible interactions between the two proteins. In the rat eye, optimedin, another olfactomedin domain protein, is strongly expressed in the tissues of the eye angle, retina, and brain. In human tissues, expression of optimedin in the tissues of the angle was significantly weaker than in the retina or brain. Indeed, our preliminary data indicate that there are significant variations in the level of expression of olfactomedin-containing genes between rat, mouse, and humans. This may have significance for animal experimental models of diseases involving these proteins.
The endothelial cells of Schlemm’s canal and some cells in the juxtacanalicular TM may have a vascular origin.4 5 6 7 There are two vascular systems in humans: the lymph vascular system and the blood vascular system. One of the main functions of the lymphatic system is to remove an excess of erythrocyte-free, protein-rich interstitial fluid that escapes from blood capillaries and return it to blood circulation. In many respects, this is reminiscent of the aqueous outflow system of the eye. The aqueous humor has similarities with lymph and the TM closely resembles a lymphatic sinusoidal network. Schlemm’s canal has an endothelial lining and transports the aqueous humor toward the blood, thereby functioning like a lymphatic collector. A divergent homeobox gene Prox1 is essential for development of the lymphatic system in mice47 and is a marker of lymphatic endothelial cells in humans.48 49 Antibodies against the Prox1 protein stain lymphatic but not blood vessels. Although PROX1 cDNA was not present among the sequenced clones in the human TM library, expression of the PROX1 gene has been detected in the human TM by RT-PCR (Malyukova I, Tomarev SI, unpublished data, 2002). Recent data demonstrate that overexpression of PROX1 in blood vascular endothelial cells in vitro induces expression of lymphatic vascular endothelial cell-specific markers and suppresses the expression of approximately 40% of the blood vascular endothelial cell-specific genes.50 Several genes that are preferentially expressed in the lymphatic versus blood vessel endothelium (matrix Gla protein, apolipoprotein D precursor, and selenoprotein P precursor)50 were found abundantly in the human TM cDNA collection (Table 1) . On the basis of these observations, we suggest that endothelial cells of the Schlemm’s canal and at least a population of TM cells may be more similar to the lymphatic endothelial cells than to the blood vascular endothelium cells.
The TM cDNA collection gives a view of part of the transcriptional repertoire of the tissue. Among these expressed genes are likely to be the loci for inherited TM-related disease and, indeed, the collection contains cDNAs for three known genes associated with glaucoma. Table 4 lists a number of genes close to known glaucoma loci that are represented in our collection. One interesting candidate is CDT6, which is located at 1p36.22, within the glaucoma locus GLC3B, and is among the 15 most abundant cDNAs in the TM collection (Table 1) . CDT6 encodes a secreted angiopoietin-like factor that is also highly expressed in human corneal stroma.51 52 Angiopoietins are the ligands for the vascular endothelial Tie2 receptors, and they are involved in vascular morphogenesis and maintenance. Several blinding diseases, including neovascular glaucoma, are related to an aberrant angiogenic response.53 The angiopoietin/Tie signaling pathway is considered to be involved in cell migration, proliferation, and survival, and reorganization of the actin cytoskeleton.54 However, CDT6 does not bind the Tie2 receptor, indicating that it does not function as a true member of the angiopoietin family.55 It has been suggested recently that expression of CDT6 may stimulate the deposition of specific extracellular matrix components and that CDT6 is a morphogen for human cornea.52 Alterations of extracellular matrix have been implicated in the pathogenesis of primary open-angle glaucoma.29 32 56 It is easy to imagine that mutations in the CDT6 gene could have profound effects on the TM leading to glaucoma. In the TM library, the most abundant cDNAs for extracellular matrix proteins correspond to myocilin, GLA, decorin, SPARC-like 1, and osteopontin (Table 2) .
Another candidate represented in among the TM cDNAs is the gene for the RERE protein located at 1p36.23. RERE contains an arginine-glutamic acid dipeptide repeat and is able to interact with the DRPLA protein, which contains a glutamine repeat and is involved in dentatorubral-pallidoluysian atrophy.57 Although no connection between DRPLA and glaucoma is known, it has been shown that DRPLA is associated with corneal endothelial degradation.58 Other abundant cDNAs from genes in the 1p36 region include myosin light chain kinase (MYLK) and ZNF9. MYLK has two products, the light chain kinase and a truncated version, telokin, and controls contractile activity in smooth muscle.59 ZNF9 encodes a zinc finger protein that binds to sterol regulatory elements and is the locus for myotonic dystrophy 2 (Online Mendelian Inheritance in Man [OMIM], 602668), a condition that includes cataract.60 61
Mutations in two mouse genes, Gpnmb and Tyrp1 were recently implicated in iris pigment dispersion and iris stromal atrophy,46 62 although no mutations were found in several human families with pigment dispersion syndrome.62 63 cDNAs corresponding to TYRP1 and GPNMB genes were present five and four times, respectively, among the sequenced TM clones and were among the most abundant 100 cDNAs in the TM library. These data may justify further screening of families with glaucoma for mutations in these genes.
It is well documented that there are circadian changes in IOP.64 Although the molecular mechanisms of mammalian circadian rhythm has not been fully clarified, mammalian Per proteins are thought to be key players. cDNA for PER1 was present once among the sequenced clones in the TM library. In addition, the collection includes three clones for KIAA0443, an uncharacterized gene product that is similar to the rat PER-interacting protein, PIPS. It has been suggested that Pips might be involved in the feedback loop or output mechanism of circadian rhythm through interaction with Per1.65 The TM collection also contains one clone for the transcription factor DEC-2, which has recently been shown to play a role in regulating the mammalian circadian clock.66
In conclusion, the identification of genes expressed in the human TM will help to elucidate the molecular mechanisms involved in normal function of the TM as well in TM disease. The TM cDNA collection identifies several interesting candidate genes for inherited glaucoma. In addition, the expression profile of TM raises the possibility that the human eye outflow pathway has some similarities to the lymphatic system.
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Acknowledgements |
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Submitted for publication October 28, 2002; revised December 11, 2002; accepted January 22, 2003.
Disclosure: S.I. Tomarev, None; G. Wistow, None; V. Raymond, None; S. Dubois, None; I. Malyukova, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Stanislav I. Tomarev, Laboratory of Molecular and Developmental Biology, National Eye Institute, Building 6, Room 2A04, 6 Center Drive MSC 2730, Bethesda, MD 20892-2730; tomarevs{at}nei.nih.gov.
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